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Author Notes:

Correspondence to: Rita Nahta, PhD, Suite 5001, 1510 Clifton Rd, Phone: 404-778-3097; Fax: 404-778-5530; rnahta@emory.edu

Subjects:

Research Funding:

R.N. gratefully acknowledges funding from the National Cancer Institute (K01CA118174 and 3K01CA118174-5S1), The Mary Kay Foundation, and the Georgia Cancer Coalition (Distinguished Cancer Scholar Award).

Keywords:

  • breast cancer
  • erbB2
  • Her2
  • Herceptin
  • resistance
  • Trastuzumab
  • cross-talk
  • lapatinib
  • pertuzumab
  • IGF-IR
  • VEGF
  • TGF beta
  • FAK

Pharmacological Strategies to Overcome HER2 Cross-talk and Trastuzumab Resistance

Tools:

Journal Title:

Current Medicinal Chemistry

Volume:

Volume 19, Number 7

Publisher:

, Pages 1065-1075

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Approximately 20–30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor crosstalk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.

Copyright information:

© 2012 Bentham Science Publishers. All Rights Reserved.

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